Evaluation of shared genetic aetiology between osteoarthritis and bone mineral density identifies SMAD3 as a novel osteoarthritis risk locus.

Sophie Hackinger,Julia Steinberg,Konstantinos Hatzikotoulas,Fernando Rivadeneira,John P Kemp,Eleni Zengini,Arthur Gilly,Andrew W Mccaskie,Katerina Trajanoska,Eleftheria Zeggini,Roger A Brooks,David M Evans ,Unnur Þorsteinsdóttir ,Graham R S Ritchie ,Þorvaldur Ingvarsson ,Unnur Styrkársdóttir ,Εvangelos Εvangelou ,Kāri Stefánsson ,J Mark Wilkinson ,Helgi Jónsson

doi:10.1093/hmg/ddx285

Abstract

Osteoarthritis (OA) is a common complex disease with high public health burden and no curative therapy. High bone mineral density (BMD) is associated with an increased risk of developing OA, suggesting a shared underlying biology. Here, we performed the first systematic overlap analysis of OA and BMD on a genome wide scale. We used summary statistics from the GEFOS consortium for lumbar spine (n = 31,800) and femoral neck (n = 32,961) BMD, and from the arcOGEN consortium for three OA phenotypes (hip, ncases=3,498; knee, ncases=3,266; hip and/or knee, ncases=7,410; ncontrols=11,009). Performing LD score regression we found a significant genetic correlation between the combined OA phenotype (hip and/or knee) and lumbar spine BMD (rg=0.18, P = 2.23 × 10−2), which may be driven by the presence of spinal osteophytes. We identified 143 variants with evidence for cross-phenotype association which we took forward for replication in independent large-scale OA datasets, and subsequent meta-analysis with arcOGEN for a total sample size of up to 23,425 cases and 236,814 controls. We found robustly replicating evidence for association with OA at rs12901071 (OR 1.08 95% CI 1.05–1.11, Pmeta=3.12 × 10−10), an intronic variant in the SMAD3 gene, which is known to play a role in bone remodeling and cartilage maintenance. We were able to confirm expression of SMAD3 in intact and degraded cartilage of the knee and hip. Our findings provide the first systematic evaluation of pleiotropy between OA and BMD, highlight genes with biological relevance to both traits, and establish a robust new OA genetic risk locus at SMAD3.

Highlights

Osteoarthritis (OA) is a degenerative disease of the joints affecting over 40% of people over 70 years [1]
Six loci associated with OA were nominally significant for FNor lumbar spine BMD (LSBMD), including the SUPTH3/CDC5L locus, which is close to RUNX2, and KLHL42/PTHLH (Supplementary Material, Table S1)
There was a significant correlation between combined OA and LSBMD, but not hip or knee OA and LSBMD or between femoral neck BMD (FNBMD) and any OA phenotype (Fig. 1)

Summary

Introduction

Osteoarthritis (OA) is a degenerative disease of the joints affecting over 40% of people over 70 years [1]. Due to a lack of therapeutic options, the main treatment strategy consists of pain management and, in severe cases, joint replacement surgery [2]. OA is a complex disorder with the 18 currently known risk loci accounting for approximately 11% of disease heritability [4]. The biggest OA genome-wide association study (GWAS) published to date was conducted by the arcOGEN consortium in a two-stage design, culminating in a total discovery sample of 7,410 cases and 11,009 controls [5,6]. Cases in the arcOGEN study had radiographic hip or knee OA 2), and approximately 80% had undergone total joint replacement surgery, indicating disease progression to a severe degree [6] Cases in the arcOGEN study had radiographic hip or knee OA (defined as a Kellgren Lawrence score ! 2), and approximately 80% had undergone total joint replacement surgery, indicating disease progression to a severe degree [6]

Methods

Results

Conclusion